Abstract The incidence of chemotherapy-related cognitive impairment (CRCI) is approximately 60% but its etiology remains unclear. There is significant overlap between chemotherapy actions and physiologic processes involved in Alzheimer?s Disease (AD)-related neurodegeneration. AD and CRCI share a genetic risk (i.e. APOE e4 genotype) and previous studies suggest that chemotherapy may accelerate the aging processes. We have consistently shown that patients with CRCI have lower brain network (?connectome?) organization. We also have preliminary evidence that chemotherapy-treated patients with a certain profile of connectome organization have higher predicted probability of Alzheimer?s Disease and its related dementias (AD/ADRD) even after controlling for apolipoprotein (APOE) genotype. It is also unknown what molecular mechanisms might contribute to this increased AD probability. Major neurodegenerative processes in AD include amyloid-beta accumulation, tau hyperphosphorylation and inflammation. CRCI has been associated with chronically elevated pro-inflammatory cytokines but few studies have evaluated cytokine levels longitudinally and none have examined the contribution of tau, amyloid-beta or their interaction with cytokine elevation in CRCI. Our preliminary work suggests peripheral tau elevation associated with CRCI. We have already collected the fMRI, medical and self-report data from our cohort of 105 participants (35 cancer patients who underwent chemotherapy treatment, 35 cancer patients who did not receive chemotherapy and 35 healthy controls) pre, post and 1 year after cancer treatments (or relevant yoked intervals). Our newly funded renewal R01 offers a unique opportunity to collect further longitudinal data on this cohort as they reach very long-term survivorship (up to 10+ years post- treatment) and begin to reach advanced age when pathologic neurodegeneration becomes more likely. This supplement will allow us address several important questions directly relevant to ADRD and will likely stimulate additional activity leading to progress on ADRD by examining longitudinal predicted probability of ADRD from pre-treatment to up to 10+ years post-treatment. Additionally, we will be able to examine the effects of chemotherapy on biomarkers of AD- related neurodegeneration.